Process for the production of cefotaxime sodium

ABSTRACT

A process for the production of 7-[2-(2-amino-4-thiazolyl)-2-syn-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (Cefotaxime) in aqueous isopropyl alcohol is provided. The synthesis provides the product in greater than 99 % HPLC purity.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from international patent applicationSerial No. PCT/IB2004/000090 filed Jan. 16, 2004, and published inEnglish on Aug. 25, 2005 as International Publication No. WO 2005/076694A2, which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the productionof7-[2-(2-aminpthiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylicacid (Cefotaxime) and its sodium salt. The synthesis of Cefotaximeincludes the reaction of2-(2-chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetyl chloride with7-aminocephalo-sporanic acid (7-ACA) in a mixture of isopropyl alcoholand water. The amino protected Cefotaxime is subsequently de-protectedusing thiourea and a mild base in aqueous isopropyl alcohol to obtainCefotaxime acid. The acid is converted into the sodium salt usingsodium-2-ethylhexanoate in of ethyl acetate, methanol and triethylamineto obtain Cefotaxime sodium in greater than 99% HPLC purity.

BACKGROUND OF THE INVENTION

Cephalosporin antibiotics inhibit bacteria by interfering with thesynthesis of essential structural components of the bacterial cell wall.They are considered as highly effective antibiotics with low toxicityand can be used for treatment of a wide variety of bacterial infections.A number of cephalosporin derivatives have been discovered withincreased potency and improved stability. Ochiai et al. (U.S. Pat. No.4,098,888) disclose cephem compounds and processes for theirpreparation. Heymes et al. (U.S. Pat. No.4,152,432) disclose3-acetoxymethyl-7-(iminoacetamido)cephalosporonic acid derivatives, inparticular cefotaxime, and process for preparing the derivatives.

7-ACA (7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid) having theformula IA:

is known, and has been proposed as starting material in varioussyntheses, in particular in the synthesis of cephalosporins. Variouscephalosporins can be obtained through the following reaction steps;

-   -   1. acylation of the 7-amino group of the cephalosporanic ring        with an optionally substituted aminothiazolyl acetic acid        wherein the amino group has been protected;    -   2. de-protecting the amino protecting group; and    -   3. optionally converting the 3-acetoxymethyl group of the        cephalosporanic ring to another group using a nucleophilic        agent.

The order of these steps may be varied as desired. Typically, theacylation of the 7-amino group of the cephalosporanic ring is carriedout with an optionally substituted aminothiazolyl acetic acid whoseamino group has been protected, followed by the de-protection of theamino group.

U.S. Pat. No. 4,767,852 discloses a process for the preparation of known2-oxyiminoacetamido-3-cephem-4-carboxylic acid derivatives, includingcefotaxime and ceftriaxone, by acylating 7-amino-3-cephem-4-carboxylicacid derivatives already substituted at the 3-position with2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate,the latter being often referred to as MAEM. Similarly, U.S. Pat. No.5,026,843 discloses a process for preparing ceftriaxone disodium salthemi-heptahydrate. As the first step in the process disclosed in thatpatent, 7-amino-cephalosporanic acid (7-ACA) already suitablysubstituted at the 3-position is acylated at the 7-position using MAEMas the acylating agent. MAEM has become the standard acylating agent forthe preparation of cephalosporins having an oximino group and a2-aminothiazolyl group in the 7-acylamido side chain. However, abyproduct of this reaction is the toxic compound, viz.,2-mercaptobenzothiazole.

U.S. Pat. No. 5,317,099 discloses a process for the synthesis ofβ-lactam derivatives such as cefotaxime and ceftriaxone in whichsilylated 7-ACA is acylated with acyloxyphosphonium chloride derivativeof 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino acetic acid, which in turnis prepared from triphenylphosphine (TPP), hexachloroethane or carbontetrachloride and 2-(2-aminothiazol-4-yl)-2-syn-methoxyimino aceticacid. However, the use of TPP as a reactant can increase the overallcost to prepare the cefotaxime.

U.S. Pat. No. 5,037,988 discloses a process for the production ofcephalosporins, in particular cefotaxime and ceftrioxane, in which anactivated form of an organic acid, i.e.,2-(2-aminothiazol-4-yl)-2-oxyiminoacetyl sulfitedialkyl-formiminiumhalide hydrohalide having Formula A is coupled with a7-aminocephalosporanic acid derivative.

The compound of Formula A was prepared by reacting2-(2-aminothiazol-4-yl)-2-oximnino acetic acid with dimethylformiminiumchloride chlorosulfite of Formula B, which in turn was prepared byreacting approximately equimolar quantities of thionyl chloride anddimethylformamide at room temperature in specific solvents only likebenzene or toluene.

U.S. Pat. No. 5,654,425 discloses a method for acylation of the 7-aminogroup of the cephalosporanic ring, according to which a 7-ACAaminothiazolyl protected adduct is prepared by acylating,the amino groupwith an aminothiazolyl acetic acid having the amino group protected witha phenyl acetyl or a phenoxy acetyl group, the amino group can bede-protected with aqueous hydrolysis in the presence of penicillin Gamidase or penicillin V amidase, respectively.

Thus, there is a need for an efficient and inexpensive synthesis ofCefotaxime having high purity.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparing and isolatingsubstantially pure sodium,7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate,having Formula VII

In one embodiment, a process is provided for the production ofCefotaxime and the sodium salt of Cefotaxime. The process includes areaction of 2-(2-chloroaceta-midothiazol-4-yl)-2-syn-methoxyiminoacetylchloride with 7-aminocephalosporanic acid (7-ACA) in aqueous isopropylalcohol to obtain an amino protected Cefotaxime having Formula V:

The chloroacetyl group of Formula V compound is de-protected usingthiourea and a mild base in a mixture of water and isopropyl alcohol.The pH of the reaction mixture is raised to about 3.0 to obtain a whiteprecipitate of Cefotaxime with high purity. The sodium salt ofCefotaxime is obtained by reacting the sodium-2-ethylhexanoate in thepresence of triethylamine and a mixture of organic solvents. Finally,Sodium,7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylateis obtained in more than 99% HPLC pure form without any unknown impurityin more than 0.1%.

These and other aspects of the invention will be apparent from theaccompanying specification. In no event, however, should the abovesummaries or the terminology employed for the purpose of describingparticular embodiments be construed as limitations on the claimedsubject matter, which subject matter is defined solely by the attachedclaims, as may be amended during prosecution.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a simple and efficient process for thepreparation of a cephalosporin, e.g., Cefotaxime Sodium (Formula VII).The process of invention uses inexpensive and readily available startingmaterials, short reaction times, and simple isolation processes toprovide Cefotaxime Sodium in excellent purity.

The process of present invention comprises protection of the exocyclicamino unctional group of2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid (Formula I) withchloroacetyl chloride in N,N-dimethylacetamide as shown in the reactionscheme below:

The chloroacetyl chloride is added at a low temperature, with stirring.After the addition is complete the temperature is allowed to rise to 30to 35° C. and stirring is continued until the amino group is completelyprotected. The crude reaction mixture is poured into water toprecipitate out the2-(2-chloroacetylaminothiazol-4-yl)-2-syn-methoxyiminoacetic acid(Formula II). The precipitate of the title compound is obtained, afterfiltration and vacuum drying, in quantitative yield.

The carboxy group of2-(2-chloroacetylaminothiazol-4-yl)-2-syn-methoxy-iminoacetic acid isconverted to an acid chloride by reacting the acid with phosphorouspentachloride at a temperature of from about −10 to about 25° C., morepreferably the reaction temperature is from about −5 to about 10° C.2-(2-Chloroacetylaminothiazol-4-yl)-2-syn-methoxyiminoacetyl chloride(Formula III);

is obtained as solid after filtration and vacuum drying. The productobtained is used for acylation in the next step, without any furtherpurification.

The synthesis of7-[2-(2-Chloroacetamidothiazol-4-yl)-2-syn-methoxyimino)-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylicacid (N-Chloroacetamido cefotaxime, (Formula V);

is carried out by acylating7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid, (Formula IV);

with 2-(2-chloroacetylaminothiazol-4-yl)-2-syn-methoxyiminoacetylchloride (Formula III) in aqueous isopropanol, in the presence of abase. Examples of suitable bases for this reaction include alkali metalcarbonate or alkali metal hydroxide. Examples of suitable bases includesodium carbonate and sodium hydroxide. The acylation reaction ismaintained at a temperature of from about −10 to about 30° C.Preferably, the reaction temperature is from about −5 to about 10° C.The acylation process is usually complete within about 15 to 20 minutes.After the acylation reaction is complete, the pH of the reaction mixtureis adjusted to about 2.0 to about 4.0, more preferrably, from about.2.5to about 3.0, using dilute hydrochloric acid solution to obtain aprecipitate of the N-chloroacetamido cefotaxime acid (Formula V). Theprecipitate obtained from the reaction is isolated by filtration.

In another embodiment, the amino group of7-[2-(2-chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylicacid is de-protected. The de-protection of the amino group is carriedout in water or a mixture of water and alcohol. Alcohols suitable forthis reaction include methanol, ethanol or isopropanol. Moreparticularly, a mixture of water and isopropanol is preferred assolvent. The chloroacetyl group from Formula V is removed in thepresence of thiourea at a pH of from about 5.0 to about 8.0, morepreferably, of from about 6.5 to about 7.5. The pH is adjusted using abase selected from the group consisting of alkali metal carbonates oralkali metal hydroxides. The reaction is carried out at temperature offrom about 10° C. to about 40° C., preferably at a temperature of fromabout 20° C. to 30° C. The reaction usually is complete in about 6 to 8hours. The pH of the reaction mixture is adjusted to about 2.0 to about4.0, most preferably, from about 2.7 to about 3.0 to obtain aprecipitate of Cefotaxime acid having Formula VI:

Cefotaxime acid is converted to cefotaxime sodium (Formula VII);

in a mixture of methanol and ethyl acetate in presence of triethylamineand sodium-2-ethylhexanonate. The product is precipitated by addition ofexcess ethyl acetate which on filtration provides final product (FormulaVII) as solid mass. The Cefotaxime Sodium prepared by the process of theinvention is obtained in good yield and high purity.

The purity of the Cefotaxime Sodium obtained by the above process isgreater than 99% (HPLC assessment) and no unknown impurity is observedin greater than 0.10%. The process repeatedly provides a product withabsorbance value not greater than 0.07 at 430 nm.

EXAMPLES

The following examples illustrate the invention, but is not limitingthereof,

Example 17-[2-(2-Chloroacetamidothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylicacid (N-Chloroacetamido cefotaxime, V) Step I:2-(2-Chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetic acid (II)

Chloroacetyl chloride (56.2 g) is added to a solution of2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetic acid (Formula I, 100 g)and 1000 ml of N,N-dimethyl acetamide at temperature of from −5° C. to5° C. The temperature of the reaction mixture is gradually increased tofrom 30° C. to 35° C. and stirred until the disappearance of thestarting material. After the reaction is complete, the mixture is pouredinto 1000 ml of cold water at 5° C. and stirred allow the product toprecipitate. The precipitate obtained is filtered, washed with water,and dried under vacuum to provide2-(2-chloro-acetamidothiazol-4-yl)-2-syn-methoxyiminoacetic acid(Formula II).

Step II: 2-(2-Chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetylchloride (III)

Phosphorus pentachloride (106 g) is added in portions to a stirredsolution of 2-(2-chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoaceticacid (Formula II, 137 g) and 1500 ml dichloromethane at temperature offrom −5 to 0° C. under nitrogen atmosphere. The reaction mixture isstirred at 0° C. for 90 minutes to obtain the acid chloride of2-(2-chloroacetamido-thiazol-4-yl)-2-syn-methoxyimino acetic acid as aprecipitate. The product obtained is used in the next step without anyadditional purification.

Step III:7-[2-(2-Chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylicacid (N-Chloroacetamido cefotaxime, V)

The 2-(2-chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetyl chloride(Formula III), obtained in Step II, is added portion-wise to a mixtureof 7-amino-cephalosporanic acid (100 g), 400 ml water, 400 mlisopropanol and sodium carbonate (27 g). The pH of the reaction mixtureis maintained at 6.5 to 7.5 by addition of sodium carbonate solution,and at a temperature of from −5 to 5° C. The progress of the acylationreaction is monitored by HPLC. After disappearance of starting material,the pH of the solution is adjusted to about 2.7 to 3.0 using dilutehydrochloric acid. This provides the reaction mixture in the form of aslurry, which is filtered and washed with water. The wet product is usedas is in the next step, i.e., de-protection of the amino function,without any additional purification.

Example 27-[2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylicacid (Cefotaxime acid, VI)

7-[2-(2-Chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxy-methyl-3-cephem-4-carboxylicacid (Formula V) (wet product from Step III of Example 1), thiourea (50g) and sodium carbonate (40 g) are suspended in a mixture of 200 mlwater and 400 ml of isopropyl alcohol at a temperature of from 20° C. to30° C. Sodium carbonate is added to the reaction mixture to obtain aclear solution. The progress of the de-protection of the chloroacetylgroup is monitored by HPLC. After completion of the de-protectionreaction, the crude solution is decolorized with active charcoal andfiltered. The pH of the filtrate is adjusted to from 2.7 to 3.0 withdilute hydrochloric acid, at temperature of from 20° C. and 30° C. toprovide a precipitate of Cefotaxime. The reaction mixture is stirred foran additional 2 hours, filtered, washed with isopropyl alcohol, anddried under vacuum to provide white color Cefotaxime acid (Formula VI)in high purity.

Example 3 Sodium,7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate(Cefotaxime sodium, VII)

Cefotaxime acid (Formula VI, 100 g) prepared in Example 2 is suspendedin a mixture of 300 ml methanol and 200 ml ethyl acetate followed byaddition of triethyl-amine (28.8 g) at a temperature of from −5° C. to5° C. The solution obtained is treated with activated charcoal (10 g)and filtered. A solution of sodium-2-ethylhexanoate (60 g) in 400 mlethyl acetate is added to the colorless filtrate at a temperature offrom −5 to 5° C. The Cefotaxime sodium is precipitated by diluting thereaction mixture with additional ethyl acetate. The slurry containingthe Cefotaxime sodium is filtered, washed with cold ethyl acetate anddried under vacuum to obtain a white material having HPLC purity morethan 99%, without any impurity greater than 0.1%.

All references cited herein are expressly incorporated herein byreference in their entirety into this disclosure. Illustrativeembodiments of this disclosure are discussed and reference has been madeto possible variations within the scope of this disclosure. These andother variations and modifications in the disclosure will be apparent tothose skilled in the art without departing from the scope of thedisclosure, and it should be understood that this disclosure and theclaims shown below are not limited to the illustrative embodiments setforth herein.

1. A process for preparing a compound of Formula (VII) comprising:

(a) contacting a compound of the Formula IV

with 2-(2-Chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetyl chloride and a base, in a solvent; to provide 7-[2-(2-chloroacetamidothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid; (b) converting 7-[2-(2-chloroacetamidothiazol-4-yl-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid into 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid in presence of a solvent and a de-protecting protecting agent; and (c) isolating the 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid.
 2. The process of claim 1, wherein the 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic is converted into sodium, 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate.
 3. The process of claim 1, wherein the solvent in step (a) comprises an aliphatic alcohol, water, or a mixture thereof.
 4. The process of claim 3, wherein the aliphatic alcohol comprises isopropyl alcohol.
 5. The process of claim 3, wherein solvent comprises a mixture of isopropyl alcohol and water.
 6. The process of claim 5, wherein volume ratio of isopropyl alcohol and water is about 1 to
 1. 7. The process of claim 1, wherein 7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (Formula IV) in step (a) is dissolved in aqueous isopropyl alcohol and an alkali metal carbonate or alkali metal hydroxide prior to addition of 2-(2-Chloroacetamido-thiazol-4-yl)-2-syn-methoxyiminoacetyl chloride.
 8. The process of claim 7, wherein the alkali metal carbonate is sodium carbonate.
 9. The process of claim 1, wherein pH of the mixture formed in step (a) is between about 6.0 to about 8.0.
 10. The process of claim 1, wherein the contact time for step (a) is between about 10 min to about 2 hours.
 11. The process of claim 1, wherein the contact temperature for step (a) is between about −5 to about 20° C.
 12. The process of claim 1, wherein pH of the mixture formed in step (b) is adjusted to about 2 to about 4 using mineral acid, after the reaction is complete.
 13. The process of claim 12, wherein the mineral acid is dilute hydrochloric acid.
 14. The process of claim 13, wherein reaction mixture is stirred for 2 hours to obtain a slurry.
 15. The process of claim 12-14, wherein the slurry is filtered and washed with water and isopropyl ether to provide 7-[2-(2-chloroacetamido-thiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid.
 16. The process of claim 1, wherein step (c) is carried out in aqueous alcohol.
 17. The process of claim 16, wherein volume ratio of isopropyl alcohol and water is about 2 to
 1. 18. The process of claim 1 (c), wherein thiourea is added to 7-[2-(2-chloro-acetamido-thiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid followed by addition of sodium carbonate to provide a clear solution.
 19. The process of claim 1, wherein reaction mixture in step (c) is stirred for about 5 to about 10 hours.
 20. The process of claim 1, wherein the reaction in step (c) is conducted at a temperature of from about 10 to about 40° C.
 21. There process of claim 1, wherein the pH of the reaction mixture in step (d) is adjusted to about 2.0 to about 4.0 using concentrated hydrochloric acid.
 22. The process of claim 21, wherein the reaction mixture is stirred for about 2 hours to provide a slurry.
 23. The process of claim 22, wherein the slurry is filtered and washed with water and isopropyl ether to provide 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid.
 24. The process of claim 2, wherein the acid is contacted with sodium-2-ethylhexanoate in a suitable solvent or solvent mixture, and a base.
 25. The process of claim 24, wherein the solvent comprises ethyl acetate and the solvent mixture comprises ethyl acetate and ethanol.
 26. The process of claim 24, wherein the base is triethylamine.
 27. The process of claim 24, wherein excess of ethyl acetate is added to get the precipitate the sodium, 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylate after the reaction.
 28. The process of claim 1, wherein sodium, 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid is obtained in more than 99% HPLC purity.
 29. A process for the preparing a compound of Formula (II)

comprising: (a) contacting a compound of the Formula (I)

with chloroacetyl chloride in presence of a solvent for a sufficient time to form 2-(2-Chloroacetylthiazolyl-4-yl-2-syn-methoxyiminoacetic acid; and (b) isolating the 2-(2-Chloroacetylthiazolyl-4-yl-2-syn-methoxyimino acetic acid.
 30. The process of claim 29, wherein the solvent in step (a) is an aliphatic amide.
 31. The process of claim 30, wherein the aliphatic amide is N,N-dimethylformamide or N,N-dimethylacetamide.
 32. The process of claim 31, wherein more preferable solvent is N,N-dimethylactamide.
 33. The process of claim 29, wherein chloroacetylchloride in step (a) is added below 5° C.
 34. The process of claim 29, wherein reaction temperature in step (a) is from about 20 to 40° C.
 35. The process of claim 29, wherein reaction mixture in step (a) is stirred for about 2 to about 6 hours.
 36. The process of claim 29, wherein water is added to the reaction mixture in step (b) to precipitate the 2-(2-Chloroacetylthiazolyl-4-yl-2-syn-methoxyiminoacetic acid, after the amino protection reaction is complete.
 37. The process of claim 36, wherein 2-(2-Chloroacetylthiazolyl-4-yl-2-syn-methoxyiminoacetic acid is filtered and dried to provide a dry powder.
 38. A process for the manufacturing a compound of Formula (III)

comprising: (a) contacting 2-(2-Chloroacetylthiazolyl-4-yl-2-syn-methoxyiminoacetic acid with phosphorous pentachloride in suitable solvent; and (b) isolation of 2-(2-Chloroacetylthiazolyl-4-yl-2-syn-methoxyiminoacetyl chloride.
 39. The process of claim 38, wherein step (a) is carried out in dichloromethane.
 40. The process of claim 38, wherein phosphorous pentachloride is mixed with dichloromethane in step (a) and added below 0° C. to 2-(2-chloroacetylthiazolyl-4-yl-2-syn-methoxyimino acetic acid.
 41. The process of claim 38, wherein contact time in step (a) is between about 30 min to about 2 hours.
 42. The process of claim 38, wherein 2-(2-chloroacetylthiazolyl-4-yl-2-syn-methoxyiminoacetyl chloride is filtered and washed with isopropyl ether in step (b) to get solid mass, which itself is used for further step. 